We seek to elucidate the interactive roles that atherosclerosis and Abeta play in the pathogenesis of co-morbid Alzheimer's disease (AD) and vascular dementia. Although, most of the field's efforts have been focused on the role of LDL, ApoE and their receptors play in AD pathogenesis, we have obtained evidence that APP/Abeta alters the expression and localization of the LDLR, such that it becomes concentrated in single perinuclear aggregate, rather than sorting to the cell surface. Other experiments suggest that Abeta induces a general defect in the MT network that likely leads to the mis-localization of some, but not all membrane proteins, including the LDLR, potentially rendering it (them) less active. We therefore propose to Test the Hypotheses that 1. APP/Abeta affects LDLR expression and intracellular localization. 2. Abeta-induced LDLR mis-localization leads to LDLR functional deficits, hyperlipidemia and atherosclerosis. The proposed experiments are significant because they may allow us to conclude that one reason why atherosclerosis, especially in the brain so often accompanies AD is because it is promoted by LDLR functional deficits induced by Abeta. Furthermore, the differences in affinity/activation of the different isoforms of ApoE for LDLR may be made more acute when the LDLR is less active, thus accounting in part for the increased risk of AD imparted by ApoE4. These findings and conclusions form the foundation for a comprehensive series of experiments to test the above hypotheses and determine whether Abeta induces the mis-sorting and functional inactivity of other important neuronal and non-neuronal proteins in the AD, particularly, growth factor receptors and the insulin receptor.
With 5 million patients nationwide and an annual cost of $140 billion and rising rapidly, Alzheimer's is a critical Health problem. Often Alzhimer's and brain atherosclerosis occur in the same patient. We have discovered a possible reason for the co-occurrence of vascular brain disease and Alzheimer's disease. Specifically we have found the Alzheimer Abeta peptide that in pathogenic form causes the neuronal damage and cognitive deficits of Alzheimer's disease also prevents the Low Density Lipoprotein Receptor from reaching the cell surface. The LDLR plays an essential role in bringing cholesterol into the cell and thus allowing the cell to function and also preventing buildup of LDL cholesterol in the blood and other fluids where it cause atherosclerosis. These results will be followed up to confirm them and establish the mechanism by which this damage to LDLR occurs. Such knowledge is essential for developing drugs against age- related Alzheimer's and vascular dementia.
|Granic, Antoneta; Potter, Huntington (2013) Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis. PLoS One 8:e60718|